Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D317/16—Radicals substituted by halogen atoms or nitro radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
  • C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• This invention relates to novel imidazole derivatives and, more particularly, to 1-(B-aryDethyl-imidazole ethers and amines having the following formula:
• R, R and R are each a member selected from the group consisting of hydrogen and lower alkyl
• X is a member selected from the group consisting of oxy and NH;
• 11 is the integer zero, 1 or 2;
• Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl and halothienyl, said substituted phenyl containing at least one phenyl substituent selected from the group consisting of halo, lower alkyl and lower alkoxy;
• Ar is a member selected from the group consisting of phenyl, substituted phenyl and u-tetralyl, said substituted phenyl containing at least one phenyl substituent selected from the group consisting of halo, lower alkyl, lower alkoxy, cyano, nitro and amino;
• R is a member selected from the group consisting of hydrogen, methyl and ethyl
• R" is a member selected from the group consisting of hydrogen and methyl
• lower alky and lower alkoxy may be straight or branch chained saturated hydrocarbons having from 1 to about 6 carbons, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like alkyls, and, respectively, the corresponding alkoxys such as methoxy, ethoxy, propoxy, isopropoxy, etc.
• the preferred lower alkyl and lower alkoxy are methyl and methoxy, respectively.
• halo refers to halogens of atomic weight less than 127, i.e., fluoro, iodo, bromo and chloro.
• the preferred substituted phenyls with regard to the symbol Ar are mono-, diand trihalophenyl, lower alkylphenyl and lower alkoxyphenyl; and mono-, diand tri-halophenyl, monoand di-(lower alkyl) phenyl, lower alkoxyphenyl, cyanophenyl, monoand di-nitrophenyl and aminophenyl with regard to the symbol Ar.
• the amines of Formula I that is, when X- is are readily obtained by the reductive amination of an appropriate 1-(aroyl-methyl)-imidazole of Formula H, wherein R R R, R" and Ar are as previously described, for example, by treating such ketone (II) with an appropriate amine of Formula III, wherein n and Ar are as previously described, in a suitable solvent, e.g., an aromatic hydrocarbon such as benzene, toluene, xylene and the like.
• a suitable solvent e.g., an aromatic hydrocarbon such as benzene, toluene, xylene and the like.
• the amination is conducted under reflux conditions and in the presence of a small amount of an appropriate acid, e.g., p-toluenesulfonic acid.
• the aromatic hydrocarbon solvent is evaporated off and the residual product (IV) is transferred to a lower alkanol solvent and reduced to the corresponding amine (I-a), for example, by treatment with a suitable reducing agent, such as a complex metal hydride, e.g., potassium borohydride, odium borohydride and the like, or by catalytic hydrogenation, e.g., by contact with hydrogen and a palladium-on-charcoal catalyst.
• a suitable reducing agent such as a complex metal hydride, e.g., potassium borohydride, odium borohydride and the like
• catalytic hydrogenation e.g., by contact with hydrogen and a palladium-on-charcoal catalyst.
• the amine product is easily recovered from the reaction mixture according to conventional isolation procedures either as the free base, or, if so desired, in the form of an acid addition salt by treatment of the base with a suitable acid.
• the ethers of Formula I that is, when -X-- is oxy, are easily prepared by the O-alkylation of an appropriate a-Ar-imidazole-l-ethanol of Formula V, wherein R, R R R, R-" and Ar are as previously described, for example, by contacting such alcohol (V), the hydroxyl of which has been preliminarily converted to alkali metal salt form by treatment with an appropriate strong base such as an alkali metal amide or hydride, with an appropriate halide of Formula VI, wherein n is as previously described, Y is halo, preferably chloro or bromo, and Ar is as previously described with the exception of aminophenyl.
• Suitable solvents for the O-alkylation procedure include the aromatic hydrocarbons, e.g., benzene, toluene, xylene and the like; the dialkylformamides, e.g., dimethylformamide and diethylformamide; ethers such as tetrahydrofuran, 1,2 dimethoxyethane and the like; and hexarnethylphosphortriamide. Elevated temperatures may be advantageously employed to accelerate the rate of reaction. As with the amines of Formula I-a, the resulting ethers I-b are easily recovered in the form of the free base or as an acid addition salt.
• the foregoing O-alkylation procedure may be illustrated by the following schematic diagram:
• the Formula I ethers, wherein Ar is arninophenyl are obtained by reduction of the corresponding nitrophenyl ethers of Formula I-b according to conventional procedures for reducing a nitro function to an amino function, for example, by catalytic hydrogenation, such as by contact with hydrogen and a palladium-on-charcoal catalyst in ethanol, or by contact with nascent hydrogen, such as is produced by the action of an appropriate metal and acid, e.g., zinc and acetic acid, iron and aqueous ammonium chloride, tin and hydrochloric acid, and the like.
• an appropriate metal and acid e.g., zinc and acetic acid, iron and aqueous ammonium chloride, tin and hydrochloric acid, and the like.
• the starting ketones (II) may be prepared by several methods of synthesis.
• the ketone (II) are obtainable from the following processes; wherein the symbols R R Y, R, R and Ar are as previously defined:
• N-acetyl-imidazole [see W. Otting, Ber. 89, 1940 (1956)]
• a compound of the formula Y-CH COAr in a suitable organic solvent, e.g., acetonitrile, and preferably under reflux conditions for a few hours.
• the solvent is subsequently evaporated off and the residue dissolved in Water, filtering if necessary.
• the aqueous solution is treated with an appropriate base, e.g., sodium bicarbonate solution, until about pH 9 to precipitate the corresponding ketone: l-aroylmethyl-imidazole.
• the resulting ketone may be dissolved in a suitable organic solvent and reprecipitated as an acid addition salt by conventional treatment with an acid; or
• (B) 2-R-4(5)-R-Imidazole and a halide of the formula YCH R --COAr are intimately contacted in a suitable solvent, e.g., dirnethylformamide, lower alkanol and the like, from which mixture the desired ketone is precipitated by addition of water.
• a suitable solvent e.g., dirnethylformamide, lower alkanol and the like
• a ketone of the formula HCR R "COAr is first brominated with liquid bromine according to conventional techniques to yield the compound BrCR R COAr which is then reacted with said 2-R'-4(5)-R"-imidazole;
• the starting alcohols (V) are also obtainable from several methods of synthesis such as the following processes; wherein the symbols R, R R Y, R, R" and Ar are as previously defined;
• the carbonyl function of the ketones (II) is reduced to a carbinol function by contact with a suitable reducing agent, for example, sodium borohydride, lithium aluminum hydride, and the like, in a suitable solvent, e.g., a lower alkanol; or
• (C) 2R'4(5)R"--imidazole is contacted with a compound of the formula in a suitable organic solvent, e.g., a lower alkanol, and in the presence of a small amount of organic base, e.g., pyridine, to yield, as a precipitate upon the addition of water, the corresponding alcohol of Formula V, in which R, R and R all equal hydrogen.
• a suitable organic solvent e.g., a lower alkanol
• organic base e.g., pyridine
• a suitable organic solvent e.g., an aromatic hydrocarbon such as benzene, toluene, xylene and the like, to which a small amount of ptoluenesulfonic 'acid may be added.
• novel compounds herein are obtained either in the form of the free bases or salts thereof.
• the salts are converted to the free basis in the usual manner, e.g., by reaction with alkali such as sodium or potassium hydroxide.
• the compounds in base form may be converted to their therapeutically useful acid addition salts by reaction with an appropriate acid, as, for example, an inorganic acid such as hydrohalic acid, i.e., hydrochloric, hydrobromic or hydroiodic acid; sulfuric, nitric or thiocyanic acid; a phosphoric acid; an organic acid such as acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, p-toluenesulfonic, salicylic, p-aminosalicylic, 2-phenoxybenzoic or Z-acetoxy benzoic acid.
• an inorganic acid such as hydrohalic acid, i.e., hydrochloric, hydrobromic or hydroi
• the subject compounds of Formula I and the acid addition salts thereof are useful agents in combatting fungi and bacteria as demonstrated by their broad spectrum of anti-fungal and anti-bacterial action.
• the data given in the following tables illustrate such activity.
• the method employed in obtaining the tabulated data is that reported by Vanbreuseghem et al., Chemotherapia, 12, 107 (1967).
• the tests on fungi were performed using Sabourauds liquid medium (1 g. of neopeptone Difco and 2 g. of glucose Difco per ml. distilled water) in 16 x 160 mm. test tubes, each containing 4.5 ml. of liquid medium, autoclaved at C. for 15 minutes.
• the drug to be tested is primarily dissolved in ethanol 50% at a concentration of 20 mg/ml. and afterwards diluted with sterile distilled water in order to obtain a concentration of 10 mg./ml. Successive decimal dilutions were made in distilled water.
• To each tube, containing 4.5 ml. of Sabourauds liquid medium 0.5 ml.
• a control tube was prepared by adding 0.5 ml. distilled water to 4.5 ml. medium. The concentration of ethanol in the control tubes was the same as in those containing l000'y and 500 ml. of the drug.
• the filamentous fungi were incubated at 25 C. for two to three weeks.
• a square block of 2 mm. side was cut and inoculated in the liquid medium.
• a three day old culture on Sabourauds liquid medium was used for yeasts.
• the inoculum was 0.05 ml. per tube. All the cultures were made in duplicate and incubated at 25 C.
• the tests on bacteria were performed on phenol red dextron broth medium (Difco) and on trypton broth medium (Difco) using the same decimal dilution technique as for fungistatic tests (1007/1111. and 10y/II11.).
• the inoculum size are 0.1 m1. from a 24 hours culture diluted in distilled water for Streptococcus pyogenes and 0.05 ml. for the other organisms.
• the results after 72 hours were rated as or 0, corresponding to the presence of the absence of growth.
• Table III hereafter illustrate such anti-bacterial action.
• this invention provides valuable compositions comprising the subject amines and ethers (I) or the acid addition salts thereof as the active ingredient in a solvent or a solid, semi-solid or liquid diluent or carrier, and, in addition, it provides an effectve method of combatting fungus or bacterial growth by use of an elfective anti-fungal or anti-bacterial amount of such amines and ethers (I) or salts thereof.
• the subject compounds can be used in suitable solvents or diluents, in the form of emulsions, suspensions, dispersions or ointment, on suitable solid or semi-solid carrier substances, in ordinary or synthetic soaps, detergents or dispersion media, if desired, together with other compounds having arachnicidal, insecticidal, ovicidal, fungicidal and/or bactericidal effects, or together with inactive additives.
• Sold carrier substances which are suitable for the preparation of compositions in powder form include various inert, porous and pulverous distributing agents of inorganic or organic nature, such as, for example, tricalcium phosphate, calcium carbonate, in the form of prepared chalk or ground limestone, kaolin, bole, bentonite, talcum, kieselghur and boric acid; powdered cork, sawdust, and other fine pulverous materials of vegetable origin are also suitable carrier substances.
• inert, porous and pulverous distributing agents of inorganic or organic nature such as, for example, tricalcium phosphate, calcium carbonate, in the form of prepared chalk or ground limestone, kaolin, bole, bentonite, talcum, kieselghur and boric acid
• powdered cork, sawdust, and other fine pulverous materials of vegetable origin are also suitable carrier substances.
• the active ingredient is mixed with these carrier substances, for example, by being ground therewith; alternatively, the inert carrier substance is impregnated with a solution of the active component in a readily volatile solvent and the solvent is thereafter elimiated by heating or by filtering with suction at reduced pressure.
• wetting and/ or dispersing agents such as pulverous preparations can also be made readily wettable with water, so that suspensions are obtained.
• Inert solvents used for the production of liquid preparations should preferably not be readily inflammable and should be as far as possible odorless and as far as possible non-toxic to warm-blooded animals or plants in the relevant surroundings.
• Solvents suitable for this purpose are high-boiling oils, for example, of vegetable origin, and lower-boiling solvents with a flash point of at least 30 C., such as, for example, isopropanol, dimethylsulfoxide, hydrogenated naphthalenes and alkylated napthalenes. It is, of course, also possible to use mixtures of solvents. Solutions can be prepared in the usual way, if necessary, with assistance of solution promoters.
• liquid forms which can be used consist of emulsions or suspensions of the active compound in water or suitable inert solvents, or also concentrates for preparing such emulsions, which can be directly adjusted to the required concentration.
• the active ingredient is, for example, mixed with a dispersing or emulsifying agent.
• the active component can also be dissolved or dispersed in a suitable inert solvent and mixed simultaneously or subsequently with a dispersing or emulsifying agent.
• semi-solid carrier substances of a cream ointment, paste or Waxlike nature, into which the active component can be incorporated, if necessary, with the aid of solution promoters and/or emulsifiers.
• Vaseline and other cream bases are examples of semisolid carrier substances.
• the active component is used in the form of aerosols.
• the active component is dissolved or dispersed, if necessary, with the aid of suitable inert solvents as carrier liquids, such as difluorodichloromethane, which at atmospheric pressure boils at a temperature lower than room temperature, or in other volatile solvents.
• suitable inert solvents such as difluorodichloromethane, which at atmospheric pressure boils at a temperature lower than room temperature, or in other volatile solvents.
• the subject compounds and compositions thereof can be applied by conventional methods.
• a fungus or bacterial growth or a material to be treated or to be protected against attack by fungus or bacterium can be treated with the subject compounds and the compositions thereof by dusting, sprinkling, spraying, brushing, dipping, smearing, impregnating or other suitable means.
• a high activity over a very high range of dilution is observed.
• suitable carriers e.g., in solution, suspension, dust, powder, ointment, emulsion, and the like forms
• concentrations of the active ingredient ranging from 0.1-10 percent by weight, based on the weight of composition employed, have been found effective in combatting fungi or bacteria. Of course, higher concentrations may also be employed as warranted by the particular situation.
• EXAMPLE H (A) To a stirred and refluxing solution of 8.3 parts of l-acetyl-imidazole in 40 parts of acetonitrile is added portionwise 10.4 parts of 4-methyl-phenacylbromide. After the addition is complete, the Whole is stirred and refluxed for 2 hours longer. The solvent is evaporated in vacuo and the residue dissolved in Water. This aqueous phase is extracted with ether and then there is added to the aqueous phase sodium carbonate solution till pH 9. An oil is separated, which solidifies on scratching. The solid is filtered off and recrystallized from hot Water (activated charcoal is added). The product is filtered off again, after cooling, and dried, yielding 1-[(4-methyl-benzoyl)-methy1]-imidazole; M.P. 133134 C.
• the hydrochloride salt is prepared in the usual manner, yielding, after two recrystallizations: first from a mixture of 2-propanol and diisopropylether and then from a mixture of methanol and diisopropylether, 2'-chloro-2-(1-imidazolyl)acetophenone hydrochloride; M.P. l86.5-189 C.
• the hydrochloride salt is prepared in the usual manner.
• the crude salt is recrystallized twice from a mixture of 2-propanol, methanol and diisopropylether.
• the free base is again liberated by treatment with an equivalent amount of sodium hydroxide and after recrystallization from a mixture of 2-propanol and diisopropylether, about 178 parts of 1-(p-fluorophenacyl) imidazole are obtained; M.P. 149'155 C.
• EXAMPLE VII To a solution of 252 parts of bromine in 400 parts of dry ether and 640 parts of dioxane is added dropwise 320 parts of methyl-Z-thienylketone, while cooling on ice and stirring. The solvent is removed at atmospheric pres sure until an internal temperature of 125 C. is reached. The residue is cooled on an ice-salt bath and 400 parts of acetonitrile are added while stirring. At an internal temperature of 0 0., there is added a hot solution of 544 parts of imidazole in 400 parts of acetonitrile: the temperature rises to 60 C. and over 30 minutes the temperature is brought to 0-5 C. The whole is further stirred first for 1% hrs. While cooling and then at reflux temperature for one hour.
• the solvent is removed at atmospheric pressure until internal temperature of 125 C.
• the residue is cooled on ice and there are added successively 800 parts of methylene dichloride and 1500 parts of water.
• the methylene dichloride solution is Washed three times with water, dried, filtered and evaporated in vacuo.
• the nitrate salt is prepared in the usual manner.
• the solid salt is filtered off and recrystallized twice: first from acetonitrile (charcoal) and then from a mixture of ethanol and diisopropylether, yielding (l-imidazolylmethyl)-2-thienyl ketone nitrate; M.P. 136 C.
• EXAMPLE V-III A solution of 50 parts of 2,4-dichloroacetophenone in 400 parts of refluxing methanol is brominated with 41.5 parts of bromine, While stirring. After the addition is complete, the mixture is cooled in an ice-bath and there are added parts of imidazole with stirring. Stirring is then continued for another 3 hours. The solvent is removed in vacuo. The residue is poured onto Water and the product 2',4'-dichloro-2-(1-imidazolyl)-acetophenone, is extracted with methylene chloride. The extract is washed with water, dried, filtered and evaporated in vacuo. From the residual oily free base, the nitrate salt is prepared in the usual manner. The precipitated 15 solid salt is filtered oif and recrystallized from water, yielding 2',4-dichloro-2- l-imidazolyl) acetophenone nitrate; M.P. 164.5 C.
• EXAMPLE TX To a stirred mixture of 150 parts of 2-methoxyacetophenone in 320 parts of ether and 160 parts of dioxane are added dropwise 160 parts of bromine. After the addition is complete, stirring is continued for 2 hours. The mixture is cooled on ice and there is added 350 parts of imidazole in 400 parts of methanol and the whole is stirred overnight. The solvents are evaporated till an internal temperature of 90 C. is reached. Then 1000 parts of water are added to the residue and the product, 2-(l-imidazolyl)-2- methoxyacetophenone, is extracted with chloroform. The extract is Washed with water and there is added an excess of 2-propanol previously saturated with gaseous hydrogen chloride.
• the precipitated salt is filtered oil? and recrystallized from a mixture of ethanol 95%, acetone and diisopropylether, yielding 2-(l-imidazolyl)-2'-methoxyacetophenone hydrochloride; M.P. 208 C.
• Example XIV The procedure of Example XIII is repeated except that an equivalent amount of an appropriate starting ketone is substituted therein to yield, as respective products, the following alcohols of Formula V, some of which have been converted to the indicated acid addition salt by treatment in the conventional manner with the appropriate acid:
• EXAMPLE XVIII To a sodium methoxide solution, prepared from 20.7 parts of sodium in 200 parts of methanol, are added suc cessively 61.2 parts of imidazole and 200 parts of dimethylformamide. The solvent is removed at atmospheric pressure, while stirring. At an internal temperature of 130 C. (all of the methanol has been removed), there are added 133 parts of a-chloromethyl-a-methyl-(p-chlorobenzyl) alcohol. The Whole is stirred for minutes longer at a temperature of 135 l40 C. After the addition of 500 parts of water, the product is crystallized. The whole is cooled on ice and the product is filtered off. It is dissolved in chloroform.
• the mixture is stirred and refluxed in an apparatus equipped with a watertrap. After 2 hours the theoretical amount of water is evolved and the remaining one-fifth portion of the solution of p-chloro-benzylamine in toluene is added.
• the reaction mixture is further stirred at reflux temperature for one hour.
• the solvent is evaporated.
• the residue is stirred three times in petroleum ether (total volume 80 parts) to remove the excess of p-chloro-ben-zylarnine.
• the residue is then dissolved in parts of ethanol and to the solution are added, portionwise, at 60 C., 4 parts of sodium borohydride. After the addition is complete, the whole is stirred at reflux temperature for 30 minutes. Then a second portion of 2.
• the hydrochloride salt is product, 1- [fi-(p-chlorobenzylamino) -phenethyl] -imid prepared in the usual manner.
• the crude salt is filtered azole, is extracted with benzene.
• the extract is washed oh and recrystallized twice: first from a mixture of ethwith water, dried and evaporated in vacuo.
• the hydrochloride salt is prepared in the usual 15 water, yielding 1- [,B (o-chlorobenzylamino)phenethyl] manner, yielding, after recrystallization from a mixture imidazole dihydrochloride; M.P.
• the aqueous filtrate is made strongly (p chlorohenzylamino)-p-methylphenethyl]imidazole, is alkaline with 5 N sodium hydroxide solution and the extracted with benzene.
• the extract is washed with water, amine product is extracted three times with dry benzene. 4,0 dried, filtered and evaporated in vacuo.
• the residue is The combined extracts are dried and evaporated. From Washed with pretroleum ether and cooled on ice. The solthe residual oily free base, the hydrochloride salt is prevent is decanted and from the residue the hydrochloride pared in the usual manner.
• the crude salt is filtered ofi salt is prepared in the usual manner, yielding after recrysand recrystallized twice: first from a mixture of ethanol, tallization from a mixture of ethanol and diisopropylether, acetone and diisopropylether and then from a mixture of 1 ⁇ ti-(p-chlorobeuzylamino) p methylphenethyl]imidethanol and acetone, yielding l-(fi-phenethylaminophenazole, dihydrochloride; M.P. 264-265 C. et'hyl)-imidazole dihydrochloride; M.P. 167-171 C.
• EXAMPLE XXVIII EXAMPLE XXV The reductive amination procedure of Example )QCVII The procedure of Example XXIV is repeated except is repeated except is repeated except that an equivalent quantity of an approthat an equivalent quantity of m-chloro-benzylamine is priate ketone of Formula H and an equivalent quantity used in place of the starting amine used therein to yield, of an appropriate amine of Formula III are substituted as the respective product, 1-[fl-(m-chlorobenzylamino) therein as starting materials to yield, as respective prodphenethyl] -imidazole dihydrochloride; M.P. 251255 C. ucts, the following imidazole amines of Formula I-a in acid addition salt form by conventional treatment with EXAMPLE XXVI the particular acid indicated below:
• EXAMPLE XXIX A solution of 140 parts of imidazole, 240 parts of 2- phenylethylene oxide, 400 parts of denatured absolute ethanol and 8 parts of pyridine is heated to refiux (an exothermic reaction occurs, requiring ice-bath moderation). Upon completion of the exotherm (about 15-30 minutes), the mixture is allowed to cool to C. Then there are added 240 parts of diisopropylether and the product is filtered ofi after cooling, triturated in ice-cold acetone, filtered oif again, washed with ice-cold acetone and then with ether, to yield l-(fi-hydroxyphenethyl) imidazole; M.P. 149150 C.
• EXAMPLE XXX A suspension of 5 parts of a-chlorophenyl)imidazole-lethanol and 1.1 parts of sodium hydride in 27 parts of dry tetrahydrofuran is stirred and refluxed for 2 hours, after which the evolution of hydrogen is ceased. Then there are added 30 parts of dimethylformamide and 4.8 parts of p-chlorobenzylchloride and the whole is stirred and refluxed for 2 hours. The tetrahydrofuran is evaporated at atmospheric pressure and the dimethylformamide solution is poured onto water. The product is extracted with benzene. The extract is washed with water, dried, filtered and evaporated in vacuo. The residue is Washed with petroleum ether.
• l-[p-chloro-fi- (pwhlorobenzyloxy)phenethy1]imidazole the nitrate salt is prepared in the usual manner from nitric acid in 2-propanol.
• the crude solid salt is filtered off and recrystallized from a mixture of 2-propanol and diisopropylether, yielding l-[pchloro-B-(p-chlorobenzyloxy)phenethyl]imidazole nitrate, M.P. 155 C.
• EXAMPLE XQCIV A mixture of 8.8 parts of cz- (p-chlorophenyl)imidazolel-ethanol and 2.1 parts of sodium hydride in 50 parts of dry tetrahydrofuran is stirred and refluxed for 18 hours. Then there are added 25 parts of dimethylformamide and stirring and refluxing is continued for 30 minutes. Then 8 parts of o-chlorobenzylchloride is added and the mixture is stirred at reflux for 4 hours. After the addition of 300 parts of water, the product is extracted with benzene (three times). The combined extracts are washed twice with water, dried and evaporated in vacuo.
• l-[p-chloro-fl-(o-chlorobenzyloxy)phenethyl]imidazole, the nitrate salt is prepared in the usual manner.
• the precipitated solid salt is filtered ofi", triturated with ether and 2-propanol and further recrystallized from a mixture of 2-propanol and ether, yielding 1-[p-chloro-B-(o-chlorobenzyloxy) phenethyl]imidazole nitrate; M.P. 125 C.
• the reaction mixture is poured onto water and the prodnet 1 [2,4 dichloro-e-(2,6 dichlorobenzyloxy)phenethyl]imidazole, is extracted with benzene.
• the extract is washed twice with water, dried, filtered and evaporated in vacuo.
• the base residue is dissolved in a mixture of acetone and diisopropylether and to this solution is added an excess of concentrated nitric acid solution.
• the precipitated nitrate salt is filtered OE and recrystallized from a mixture of methanol and diisopropylether, yielding 1- [2,4 dichloro-B-(2,6 dichlorobenzyloxy)phenethyl] imidazole nitrate; M.P. 179 C.
• EXAMPLE XL A mixture of 8.8 parts of a-(p-chlorophenyDimidazole-l-ethanol and 2.1 parts of sodium hydride in 35 parts of 2,6-dichlorobenzyl chloride is stirred and refluxed for 18 hours. Then there are added 9.5 parts of 2,6-dichlorobenzyl chloride in 25 parts of dimethylformamide and stirring and refluxing is continued for 2 hours. The reaction mixture is cooled and the product is extracted with 80 parts of benzene. The extract is washed four times with water, dried, filtered and evaporated.
• EXAMPLE XLI A mixture of 8.7 parts of ot-(2,4-dichlorophenyl)-imidazole-l-ethanol hydrochloride and 3.4 parts of sodium hydride in 40 parts of benzene and 35 parts of dimethylformamide is stirred while cooling on ice (solvents are previously dried azeotropically). First there are added 3 parts of manganese dioxide, followed by the addition of 8 parts of p-nitrofluorobenzene and the whole is stirred for 3 hours at room temperature. The reaction mixture is filtered over hyflo and water is added. The product is extracted with benzene. The extract is dried, filtered and 27 evaporated in vacuo.
• the nitrate salt is prepared in the conventional manner in acetone.
• the precipitated solid salt is filtered olf and recrystallized from a mixture of methanol and diisopropylether, yielding 1 [2,4-dichloro-f3-(p-nitrophenoxy)phenethyl]imidazole nitrate; M.P. 167 C.
• the nitrate salt is prepared in the conventional manner in dry ether.
• the precipitated solid salt is filtered off and recrystallized from a mixture of methanol and diisopropylether, yielding 1 [2,4-dichloro-B-(p-methoxybenzyloxy)phenethyl] imidazole nitrate; M.P. 148 C.
• the precipitated solid salt is filtered off and recrystallized from a mixture of 2-propanol and diisopropylether, yielding 1 [p-chloro-fi-(pmethylbenzyloxy)phenethyl]-imidazole hydrochloride hydrate; M.P. 134.5 C.
• EXAMPLE XLIV A mixture of 7.7 parts of a-(2,4-dichlorophenyl)-imidazole-ethanol and 1.7 parts of sodium hydride in 40 parts of benzene and 35 parts of dimethylformamide is stirred while cooling on ice (solvents are previously dried azeotropically). First there are added 3 parts of manganese dioxide, followed by the addition of 10.1 parts of 2,4- dinitrochlorobenzene and the Whole is stirred for 3 hours at room temperature. The reaction mixture is filtered over hyflo and water is added.
• Example XLVIII The nitro-to-amine reduction procedure of Example XLV is repeated using an equivalent amount of each of the two nitro derivatives obtained in Example XLVII as starting materials, namely, l-[fi-(p-nitrophenoxy)-a,a-dimethylphenethyl]imidazole nitrate and l-[fl(o,p-dinitrophenoxy) a,ct dimethylphenethyl]imidazole nitrate, t yield, as respective products, the corresponding p-aminophenoxy and o,p-di
• EXAMPLE XLIX parts of p-chlorophenacylbromide are added dropwise to 250 parts of Z-methylimidazole in 500 parts of dimethylformamide at a temperature between 5 and 15 C. After the addition is complete, the Whole is stirred first for two hours on ice and further overnight at room temperature. Then 2000 parts of Water are added. The precipitated product is filtered off, and recrystallized twice from dimethylformamide, yielding 4' chloro 2-(2-methyl-limidazolyl)acetophenone; M.P. 209.5 C.
• EXAMPLE L To 290 parts of 2-ethylimidazole in 500 parts of dimethylformamide are added portionwise 140 parts of pchlorophenacylbromide, while cooling on ice (5 -15 C.). After the addition is complete, the whole is further stirred overnight and then 2000 parts of water are added. The precipitated product is filtered oil? and taken up in 16(10 parts of toluene. Water is removed azeotropically and filtered While hot. After cooling the product is precipitated. It is filtered off and recrystallized from dimethylformamide 50%, yielding 4-chloro2-(Z-ethyl-l-imidazolyl) acetophenone; M.P. C.
• EXAMPLE LIII To a solution of 37 parts of 4'-chloro-2-(2-ethyl-1-imidazolyl)acetophenone in 120 parts of methanol are added 1.5 parts of sodium borohydride in three portions, while cooling (525 C.). The whole is stirred first for 2 hours on ice and further for one hour at reflux temperature. Then about 80 parts of methanol are removed by evaporation, and 300 parts of Water are added to the residue. The aqueous phase is acidified to pH 3, refluxed for 15 minutes and made alkaline, whereupon the product is precipitated. It is filtered OE and recrystallized from toluene, yielding a (p-chlorophenyl)-2-ethyl-imida2ole-1-ethanol; M.P. 151.5" C.
• EXAMPLE LV (A) To a stirred and cooled (5 C.) mixture of 2.25 parts of sodium hydride 50% in parts of hexamethylphosphortriamide is added a solution of 9.6 parts of a-(pchlorophenyl)-2-methyl-imidazole-l-ethanol in 40 parts of hexamethylphosphortriamide. Upon completion, the cooling-bath is removed and the whole is heated to 45 C. After stirring for 30 minutes at that temperature, the mixture is cooled again to 5 C. and there are added 11 parts of 2,4-dichlorobenzyl chloride. After the addition is complete, the whole is stirred overnight at room temperature and 300 parts of water are added. The product is extracted three times with 120 parts of ether.
• EXAMPLE LVI (A) To a stirred and cooled (5 C.) solution of 2.25 parts of sodium hydride 50% in 10 parts of hexamethylphosphortriamide is added slowly a solution of 10.5 parts of a-(p-chlorophenyl)-2-ethyl-imidazole-l-ethanol in 40 parts of hexamethylphosphortriamidc. Upon completion, the whole is warmed to 45 C. and stirred at this temperature for one hour. After cooling againto 5 C., there are added 9.8 parts of 2,fi-dichlorobenzylchloride and stirring is continued for 3 hours.
• Example LVII The O-alkylation procedure of Example LVI is repeated, except that an equivalent amount of an appropriate alcohol obtained from Examples LII, LIII and LIV and an equivalent amount of an appropriate halide of the Formula Y(CH Ar are substituted therein as starting materials, to yield, as respective products, the following ethers of Formula I-b in the form of a nitrate salt:
• compositions according to this invention are employed in those forms which are customarily used for fungus or bacteria control, for example, as suspensions, dusting powders, solutions, ointments and the like.
• the following will further illustrate the invention, the parts being parts by weight unless otherwise specified:
• EXAMPLE LXI (A) 18.7 parts of l-[2,4-dichloro-p-(2,4-dichlorobenzy1oxy)phenethyl]imidazole nitrate are suspended in 300 parts of water. The suspension is alkalized with parts of sodium hydroxide solution 10 N and shaken for 5 minutes. The liberated base is extracted with chloroform (successively 115, 37.5 and 37.5 parts). The combined extracts are evaporated on a water-bath; a yellow oil is obtained, which solidifies upon dilution with about 40 parts of petroleumether. The product is filtered off and dried for 16 hours at 50 C. in vacuo, yielding l-[2,4-dichloro-B-(2,4- dichlorobenzyloxy)phenethyll-imidazole; M.P. 79.4" C.
• EXAMPLE LXiI To a suspension of 4.5 parts of sodium methoxide solution 30% in 15 parts of dirnethylforrnarnide and 16 parts of benzene are added 2 parts of imidazole. The solvent is distilled off till an internal temperature of 130 C. is reached. Then there is added a solution of 5.4 parts of a-(bromomethyl) 3,4 dichlorobenzoyl alcohol in 5.5 parts of benzene (temperature: 130 to C.) and the solvent is distilled off. The temperature is brought again to 130 C. and then cooled slowly to 40 C. Diisopropylether (32 parts) is added, followed by the addition of 50 parts of water and upon cooling, the product is crystallized.
• vIt is filtered off, washed with ether and boiled for a few minutes in a mixture of 25 parts of dimethylformamide and 5 parts of water. The product is crystallized again at room temperature and separated, yielding tat-(3,4 dichlorophenyl)imidazole 1 ethanol; M.P. 148.7 C.
• EXAMPLE LXIII To 4.5 parts of sodium methoxide solution 30% in 15 parts of dimethylformamide and 16 parts of benzene are added 2 parts of imidazole and the solvent is distilled off till a temperature of 130 C. is reached. Then there is added dropwise a solution of 5.4 parts of a-(bromomethyl)-2,6-dichlorobenzyl alcohol in 4 parts of benzene at a temperature of C. Upon completion, the temperature is brought again to C. The reaction mixture is cooled gradually to 40 C. and there are added successively 50 parts of water and 32 parts of diisopropylether, whereupon the product is crystallized.
• EXAMPLE LXIV To a solution of 4.5 parts of sodium methoxide solution 30% in 16 parts of benzene and 15 parts of dimethylformamide are added 2 parts of irnidazole. The solvent is distilled off till an internal temperature of 130 C. is reached. Then there is added dropwise a solution of 5.5 parts of a-(bromomethyl)-2,5-dichlorobenzyl alcohol in 12 parts of benzene, whereupon the temperature falls to 110 C. After addition is complete, the temperature is brought again to 130 C. to remove the solvent. The reaction mixture is cooled slowly to 50 C. and there are added 100 parts of water and 40 parts of diisopropylether. On further cooling to room temperature, the product is crystallized. It is filtered ofif, washed successively with ether and acetone and recrystallized from a mixture of dimethylformarnide and water (minimal quantities), yielding a (2,5 dichlorophenyl)imidazole 1 ethanol;
• EXAMPLE LXV To a stirred and cooled solution of 3.1 parts of mchloroacetophenone in 8 parts of dry ether and 4 parts of dioxane is added dropwise 3.2 parts of bromine, while keeping the temperature below 5 C. Upon completion, there is added dropwise a solution of 6.8 parts of imidazole in 8 parts of methanol (temperature: below 5 C.). The whole is stirred for 16 hours and then poured onto 100 parts of water, whereupon the product is crystallized. It is filtered off, taken up in a minimum of acetone and acidified with concentrated nitric acid.
• the precipitated 33 nitrate salt is filtered E and recrystallized from ethanol, yielding 3'-chloro-2-(l-imidazolyl)-acetophenone nitrate; M.P. 179.7 C. Conventional treatment with alkali affords the corresponding free base.
• EXAMPLE LXVI To a stirred and cooled (ice-bath) suspension of 10.2 parts of imidazole in 10 parts of dimethylformamide is added portionwise a solution of 6 parts of 2-bromo-4'- chloro-2-methylpropiophenone (described in CA. 55, 442c) in 10 parts of dimethylformamide at a temperature of 3-5 C. Upon completion, stirring is continued for 2 hours in an ice-bath. The cooling-bath is removed and the whole is stirred for 25 hours at room. temperature. The reaction mixture is poured onto 250 parts of water, whereupon the product is crystallized. It is filtered off and dissolved in acetone. The solution is acidified with a concentrated nitric acid solution.
• the precipitated salt is filtered oh. and recrystallized from ethanol, yielding 4'- chloro-2-(l-imidazolyl)isobutyrophenone nitrate; M.P. 178.2 C.
• Conventional treatment with alkali yields the corresponding free base.
• the precipitated solid nitrate salt is filtered off, triturated in cold acetone and filtered off again.
• the crude salt is taken up in a small amount of boiling methanol. About 4 parts of acetone are added, followed by the addition of diisopropylether till turbid. Upon cooling to room temperature, the crystallized salt is filtered off and dried, yielding 1 [3,4 dichloro fi-(2,4-dichlorobenzyloxy) phenethyl]imidazole nitrate; M.P. 142.2 C.
• Example LXIX The O-alkylation procedure of Example LXVIII is repeated except that an equivalent quantity of an appropriate alcohol of Formula V and an equivalent quantity of an appropriate halide of Formula VI are substituted therein as starting materials to yield, as respective products, the following imidazole ethers of Formula I-b in the form of a nitrate salt:
• the crystallized nitrate salt is filtered off, triturated in ice-cold acetone and recrystallized from ethanol and diisopropylether, yielding 1-[2,4,6- trichloro-B-(2,6 dichlorobenzyloxy)phenethyl]imidazole nitrate; M.P. 180.3 C.
• the crystallized salt is filtered off and recrystallized from a mixture of ethanol and diisopropylether, yielding l-[2,4-dichloro-5-(3,4-dimethylbenzyloxy) phenethylfimidazole nitrate; M.P. 138.2 C.
• EXAMPLE LXXIV To a stirred and Warm suspension of 1.8 parts of sodium hydride 50% in 36 parts of tetrahydrofuran is added portionwise a solution of 7.7 parts of a-(2,4-dichlorophenyl)imidazole-l-ethanol in 10 parts of dimethylformamide at 50 C. Upon completion, stirring is continued for 2 hours at reflux temperature. Then there are added 12 parts of p-iodobenzyl bromide and stirring and refluxing is continued for another 10 hours. The reaction mixture is diluted with 160 parts of ether and stirred for 15 minutes. The solution is Washed five times with Water and acidified with an excess of concentrated nitric acid solution.
• the crystallized solid salt is filtered oil and recrystallized from a mixture of ethanol and diisopropylether, yielding 1-[2,4-dichloro-[3-(p-iodobenzyloxy)phen ethyl] imidazole nitrate; 177.6 C.
• the crystallized salt is filtered off and recrystallized from a mixture of ethanol and diisopropylether, yielding a-[1-(2,4-dichlorophenyl)- 2-(1-imidazolyl)ethoxy] p tolunitrile nitrate; M.P. 176.2 C.
• the crystallized solid nitrate salt is filtered off, triturated in ice-cold acetone and recrystallized from ethanol and diisopropylether, yielding 1-[2,4-dichloro-fi-(2,4,6 trichlorobenzyloxy)phenethyl]imidazole nitrate; M.P. 180.1 C.
• EXAMPLE LXXIX This example demonstrates a method of preparing those ketones of Formula II obtained by the alkylation of 2- 4(5)-dimethylimidazole and a halide of the Formula YCR R COAr as the alkylating agent.
• EXAMPLE LXXX (A) 1.5 parts of sodium borohydride are added portionwise to a cooled mixture of 24.8 parts of 4-chloro-2- (2,4-dimethyl-l-imidazolyl)acetophenone in 120 parts of methanol at 5 C. Upon completion, stirring is continued for one hour on ice and one hour at reflux temperature. Then 80 parts of methanol are evaporated off and to the residue are added 200 parts of water. The aqueous phase is acidified to pH 2 and refluxed for minutes. The solution is basified again and 80 parts of diisopropylether are added.
• the crystallized nitrate salt is filtered off and recrystallized from a mixture of 24 parts of ethanol and 160 parts of diisopropylether, yielding l-[p-chloro-fi-(ZA- dichlorobenzyloxy)phenethyl]-2,4 dimethylimidazole nitrate; M.P. 145.1 C.
• Example XXVII The reductive amination procedure of Example XXVII is repeated except that an equivalent quantity of the appropriate ketone obtained in Example LXXIX and an equivalent amount of an appropriate amine of Formula III are substituted therein as starting materials to yield, as respective products, the following imidazole amines of Formula I-a in acid addition salt form by conventional treatment with the particular acid indicated:
• EXAMPLE LXXXIV 37.8 parts of methyl-2-thienyl-ketone are brominated with 48 parts of bromine in 48 parts of dioxane and 96 parts of dry ether, While cooling and stirring. The solvent is removed in vacuo. To the residue is added 60 parts of ethylene glycol in 160 parts of toluene and a few crystals of p-toluenesulfonic acid. The whole is stirred and refluxed in an apparatus equipped with a watertrap for 15 hours. The reaction mixture is cooled and the toluene layer is separated, washed once with potassium carbonate solution and once with water, dried, filtered and evaporated in vacuo. The oily residue is distilled in vacuo from potassium carbonate, yielding 2-(brornomethyl)-2- (Z-thienyl)-l,3-dioxolan; B.P. 95 C. at 0.6 mm. pressure.
• EXAMPLE LXXXV 462 parts of o-chloro-acetophenone are brominated with 48 parts of bromine in 48 parts of dioxane and 96 parts of dry ether, while cooling and stirring. The solvent is removed in vacuo. To the residue is added 60 parts of ethylene glycol in 160 parts of toluene and a few crystals of p-toluenesulfonic acid. The whole is stirred and refluxed in an apparatus equipped with a water trap for 15 hours. The reaction mixture is cooled and the toluene layer is separated, washed once with potassium carbonate solution and once with water, dried, filtered and evaporated in vacuo.
• EXAMPLE XCI 89.4 parts of 2,3,4-trichloroacetophenone are brominated with 64 parts of bromine in 96 parts of dioxane and 200 parts of dry ether, while cooling and stirring. The solvent is removed in vacuo. To the residue is added parts of ethylene glycol in 320 parts of toluene and a few crystals of p-toluenesulfonic acid. The Whole is stirred and refluxed in an apparatus equipped with a water trap for 15 hours. The reaction mixture is cooled and the toluene layer is separated, Washed once with potassium carbonate solution and once with water, dried, filtered and evaporated in vacuo.
• the oily residue is distilled in vacuo from potassium carbonate, yielding a distillate boiling at 152 C. at 1 mm. pressure. This distillate solidifies on triturating in 2-propanol. The solid product is filtered off and recrystallized from 2-propanol, yielding 2-(brorn0- methyl) 2 (2,3,4-trichlorophenyl)-l,3-dioxolane; M.P. 59.5 C.
• EXAMPLE XCIII 46.2 parts of m-chloro-acetophenone are brominated with 48 parts of bromine in 48 parts of dioxan and 96 parts of dry ether, while cooling and stirring. The solvent is removed in vacuo. To the residue is added 60 parts of ethylene glycol in 160 parts of toluene and a few crystals of p-toluenesulfonic acid. The whole is stirred and refluxed in an apparatus equipped with a Watertrap for 15 hours. The reaction mixture is cooled and the toluene layer is separated, washed once with potassium carbonate solution and once with Water, dried, filtered and evaporated in vacuo.
• the oily residue is distilled in vacuo from potassium carbonate, yielding 2-brornornethyl-2-(in-chlorophenyl)-1,3-dioxolan; B.P. 149 C. at 0.2 mm. pressure.

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